M. Abrahamovych, O. Abrahamovych, O. Fayura, S. Tolopko, M. Ferko
Danylo Halytsky Lviv National Medical University
Introduction. It is known that liver cirrhosis (LC) is a chronic diffuse liver disease, the severity of which is manifested by the restructuring of its parenchyma in the form of nodular transformation and fibrosis due to necrosis of hepatocytes, the appearance of shunts between the portal and central veins and liver failure. Oxidative stress is one of the primary pathogenetic links of the LC onset.
The aim of study. To determine the content of some endothelium-dependent vasoactive substances in the blood of patients, depending on the liver cirrhosis severity and the organism’s redox system state.
Materials and methods. 81 patients (26 females (32.1 %), 55 males (67.9 %) aged 27 to 73 years (mean age – 46.9 ± 10.8 years) were included in the randomized trial with the preliminary stratification by the presence of LC (experimental group – EG). All of them were hospitalized and treated at the Department of Internal Medicine N 1 at Danylo Halytsky Lviv National Medical University and the Gastroenterology Department of Lviv Regional Clinical Hospital – Lviv Regional Hepatology Center. We also examined 20 practically healthy persons (8 females (40.0 %), 12 males (60.0 %)) aged 19 to 70 years (mean age – 41.8 ± 4.2 years) from which a control group (CG) was formed.
All patients underwent a comprehensive clinical laboratory and instrumental examination of all organs and systems in accordance with the requirements of the modern medicine. According to the results of the examinations, all the patients of the EG were divided into 3 groups, according to the LC severity by the criteria of C. H. Child – R. N. Pugh – in the first (class A) was 19, in the second (class B) – 29, in the third (class C) – 27 persons.
To study the concentration of some endothelium-dependent vasoactive substances in blood of the cirrhotic patients, the content of endothelin-1, cyclic guanosine monophosphate (cGMP), renin, aldosterone, and also natriuretic peptide were determined using standard methods. The activity of catalase and content of thiobarbituric acid (TBA) products, including malondialdehyde (MDA), was studied to determine the redox system state.
The actual material was handled on a personal computer in Exel 2010, Statistica 6.0, RStudio v. 1.1.442 and R Commander v.2.4-4 using descriptive statistics. The results obtained in the case of normal distribution were presented as M ± σ, n – the number of patients examined in the group, in case of abnormal distribution – Me [25,0 %; 75.0 %]. The difference was considered statistically significant if p < 0.05.
Results. In accordance with the results of the study, it was found that the activity of catalase in the cirrhotic patients significantly (p < 0.001) decreased, and content of MDA content significantly (p < 0.001) increased with the LC severity increase according to the criteria of C. H. Child – R. N. Pugh. It testifies the reduction of antioxidant activity and enhancement of the reactive oxygen species activity with the formation of such toxic substances as MDA in the blood of this category of persons confirming the redox homeostasis disorders. It leads to the impaired functioning of the endothelial cells that are one of the most sensitive to the reactive oxygen species cells. As a result, NO-dependent vasodilatation, increased endothelin-1 synthesis, activation of the renin-aldosterone system, whose effect is negligible, since the decreased sensitivity of the vascular receptors to the influence of endogenous vasoconstrictors, increase of the content of natriuretic peptide, due to the inhibition of renin and aldosterone secretion, as well as a direct effect on the smooth muscle cells of the vascular wall. This is confirmed by the increase of the content of endothelin-1, cGMP, renin, aldosterone, natriuretic peptide in the blood of this category of patients with the LC increasing severity according to the criteria of
C. H. Child – R. N. Pugh.
Conclusions. The liver significantly influences the endothelium state due to the role of oxidative stress in the metabolisms of NO, endothelin-1, natriuretic peptide, renin-aldosterone system. The cirrhotic patients revealed the increase in malondialdehyde and the decrease in catalase activity with the disease severity increase according to the criteria of C. H. Child – R. N. Pugh. It evidences the significant abnormalities in the redox homeostasis of such patients, and subsequently leads to the endothelial dysfunction with impaired metabolism of vasoactive humoral-metabolic substances in the blood of patients. In particular, them become the prerequisite for the occurrence of extrahepatic comorbid syntropic lesions, that significantly complicate the underlying disease course.
- Аbrahamovych МО, Аbrahamovych OO. Classification of liver cirrhosis: retrospective view on a problem and its modern solution taking into account the syntropic co- and polymorbid lesions of the patient. Med Transport Ukr. 2013;2:10-16. (Ukrainian).
- Abrahamovych OO, Abrahamovych MO. Plasma endothelin-1 levels in patients with diffuse liver lesions. Practical M 2011;17(4);99-103. (Ukrainian).
- Abrahamovych OO, Fayura OP, Abrahamovych UO. Comorbidity: a Modern View on the Problem; Classification (second notice). Lviv Clinical Bulletin. 2016;1(13):31-39. (Ukrainian). https://doi.org/10.25040/lkv2016.01.031
- Abrahamovych OO, Fayura OP, Abrahamovych UO. Comorbidity: a Modern View on the Problem; Classification (first notice). Lviv Clinical Bulletin. 2015;4(12):56-64. (Ukrainian). https://doi.org/10.25040/lkv2015.04.056
- Zhdan VM, Katerenchuk IP, Shumeiko IF, Vakulenko KE, Katerenchuk OI. Diagnostic and prognostic value of determination of brain natriuretic peptide in case of heart failure and other cardiac conditions: methodical recommendations. Ukrainian Medical Dental Academy; 2009, (Ukrainian).
- Korolyuk MA, Ivanova LI, Mayorova IH, Tokarev VE. A method for determining the catalase activity. Laboratory Business. 1983;10:16-18. (Russian).
- Parnes EY. Liver Cirrhosis. Rus Med J. 1999;1(1):45-51. (Russian).
- Timirbulatov RR, Seleznev EI. A method of increasing the intensity of free radical oxidation of lipid-containing blood components and its diagnostic value. Laboratory Business. 1981;4:209-211. (Russian).
- Abrahamovych O, Abrahamovych M, Tolopko S, Fayura O, Ferko M. Character and Frequency of the Variations of Co- and Polymorbid Syntropic Extrahepatic Lesions and Their Dependence on the Hepatopulmonary Syndrome Severity Degree in Cirrhotic Patients. Georgian Medical News. 2016;11(260):34-41.
- Abrahamovych OO, Abrahamovych MO, Dovhan YP, Ferko MR, Tolopko SYa, Fayura OP. Ultrasound Doppler-flowmetric signes of portal hypertension in patients with liver cirrhosis, complicated with edematous-ascitic syndrome. Gastroenterologia Polska. 2013;20(4):139-142.
- Boyer TD. Tolvaptan and hyponatremia in a patient with cirrhosis. Hepatology. 2010;51:699. https://doi.org/10.1002/hep.23522
- Castells A, Saló J, Planas R et al. Impact of shunt surgery for variceal bleeding in the natural history of ascites in cirrhosis: a retrospective study. Hepatology. 1994;20:584. https://doi.org/10.1002/hep.1840200306
- Cooper SA, Whaley-Connell A, Habibi J, Wei Y, Lastra G, Manrique C, Stas S et al. Renin-angiotensin-aldosterone system and oxidative stress in cardiovascular insulin resistance. Am J Physiol Heart Circ Physiol. 2007;293(4):2009-2023. https://doi.org/10.1152/ajpheart.00522.2007
- Federico A, Conti V, Anno GR, Dallio M. A Long-term Treatment with Silybin in Patients with Non-alcoholic Steatohepatitis Stimulates Catalase Activity in Human Endothelial Cells. In Vivo. 2017;31(4):609-618. https://doi.org/10.21873/invivo.11101
- Ghandhi CR, Stephenson K, Olson MS. Endothelin, a potent peptide agonist in the liver. J Biol Chem. 1990;265(4):17432-17435.
- Grace JA, Klein S, Herath CB, Granzow M, Schierwagen R, Masing N et al. Activation of the MAS receptor by angiotensin-(1-7) in the renin-angiotensin system mediates mesenteric vasodilatation in cirrhosis. Gastroenterology. 2013;145:874-884. https://doi.org/10.1053/j.gastro.2013.06.036
- Gracia-Sancho J, Russo L, Garcia-Caldero H, Garcia-Pagan JC, Garcia-Cardena G, Bosch J. Endothelial expression of transcription factor Kruppel-like factor 2 and its vasoprotective target genes in the normal and cirrhotic rat liver. Gut. 2011;60(4):517-524. https://doi.org/10.1136/gut.2010.220913
- Ishikawa T, Seki K. The association between oxidative stress and endothelial dysfunction in early childhood patients with Kawasaki disease. BMC Cardiovasc Disord. 2018;18(1):30. https://doi.org/10.1186/s12872-018-0765-9
- Iwakiri Y, Groszmann RJ. Vascular endothelial dysfunction in cirrhosis. J Hepatol. 2007;46(5):927-934. https://doi.org/10.1016/j.jhep.2007.02.006
- Iwakiri Y. The molecules: mechanisms of arterial vasodilatation observed in the splanchnic and systemic circulation in portal hypertension. J Clin Gastroenterol. 2007;41(3 Suppl):S288-S294. https://doi.org/10.1097/MCG.0b013e3181468b4c
- Kansagra C, Kumar A, Abhisheka T, Joshi N, Sukanya B, Sandip S et al. NT Pro-BNP Levels in Patients With Cirrhosis: Correlation With Cardiovascular Dysfunction and Severity of Disease. Clin Gastoenterol Hepatol. 2015;13(1):214. https://doi.org/10.1016/j.cgh.2014.09.007
- Koch DG, Bogatkevich G, Ramshesh V, Lemasters JJ, Uflacker R, Reuben A. Elevated levels of endothelin-1 in hepatic venous blood are associated with intrapulmonary vasodilatation in humans. Dig Dis Scien. 2012;57(2):516-523. https://doi.org/10.1007/s10620-011-1905-6
- Li S, Tan HY, Wang N, Zhang ZJ, Lao L, Wong CW et al. The Role of Oxidative Stress and Antioxidants in Liver Diseases. Int J Mol Sci. 2015;16(11):26087-26124. https://doi.org/10.3390/ijms161125942
- Licata G, Tuttolomondo A, Licata A et al. Clinical Trial: High-dose furosemide plus small-volume hypertonic saline solutions vs. repeated paracentesis as treatment of refractory ascites. Aliment Pharmacol Ther. 2009;30:227. https://doi.org/10.1111/j.1365-2036.2009.04040.x
- Locatelli F, Del Vecchio L, Cavalli A. Inhibition of the renin-angiotensin system in chronic kidney disease: a critical look to single and dual blockade. Nephron Clin Pract. 2009;113:286-293. https://doi.org/10.1159/000235946
- Luu AZ, Chowdhury B, Al-Omran M, Teoh H, Hess DA, Verma S. Role of Endothelium in Doxorubicin-Induced Cardiomyopathy. J Am Coll Cardiol Basic Trans Science. 2018;3(6):861-870. https://doi.org/10.1016/j.jacbts.2018.06.005
- McDermott VG, England RE, Newman GE. Case report: bleeding gastric varices secondary to splenic vein thrombosis successfully treated by splenic artery embolization. Br J Radiol. 1995;68:928. https://doi.org/10.1259/0007-1285-68-812-928
- Niki E. Lipid peroxidation: physiological levels and dual biological effects. Free Radic Biol Med. 2009;47(5):469-84. https://doi.org/10.1016/j.freeradbiomed.2009.05.032
- Ou HY, Huang TL, Chen TY et al. Emergency splenic arterial embolization for massive variceal bleeding in liver recipient with left-sided portal hypertension. Liver Transpl. 2005;11:1136. https://doi.org/10.1002/lt.20543
- Pålsson B, Hallén M, Forsberg AM, Alwmark A. Partial splenic embolization: long-term outcome. Langenbecks Arch Surg. 2003;387:421. https://doi.org/10.1007/s00423-002-0342-6
- Possomato-Vieira JS, Khalil RA. Mechanisms of Endothelial Dysfunction in Hypertensive Pregnancy and Preeclampsia. Adv Pharmacol. 2016;77:361-431. https://doi.org/10.1016/bs.apha.2016.04.008
- Pugsley MK. The angiotensin-II (AT-II) receptor blocker olmesartan reduces renal damage in animal models of hypertension and diabetes. Proc West Pharmacol Soc. 2005;48:35-38.
- Rajagopalan S, Kurz S, Münzel T, Tarpey M, Freeman BA, Griendling KK, Harrison DG. Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation. Contribution to alterations of vasomotor tone. J Clin Invest. 1996;97:1916-1923. https://doi.org/10.1172/JCI118623
- Rosemurgy AS, Goode SE, Zwiebel BR et al. A prospective trial of transjugular intrahepatic portasystemic stent shunts versus small-diameter prosthetic H-graft portacaval shunts in the treatment of bleeding varices. Ann Surg. 1996;224:378. https://doi.org/10.1097/00000658-199609000-00014
- Rosenkranz-Weiss P, Sessa WC, Milstien S, Kaufman S, Watson CA, Pober JS. Regulation of nitric oxide synthesis by proinflammatory cytokines in human umbilical vein endothelial cells. Elevations in tetrahydrobiopterin levels enhance endothelial nitric oxide synthase specific activity. J Clin Invest. 1994;93(5):2236-2243. https://doi.org/10.1172/JCI117221
- Runyon BA. Ascites and spontaneous bacterial peritonitis. In: Sleisenger and Fordtran’s Gastrointestinal and Liver Disease, Pathophysiology/Diagnosis/Management, 7th ed. Feldman M, Friedman LS, Sleisenger MH, editors. WB Saunders, Philadelphia, 2002. 1517 p. https://doi.org/10.1016/B978-1-4160-6189-2.00091-3
- Schuppan D, Afdhal NH. Liver Cirrhosis. Lancet. 2008;371(9615):838-851. https://doi.org/10.1016/S0140-6736(08)60383-9
- Sessa WC. eNOS at a glance. J Cell Sci. 2004;117(Pt 12):2427-2429. https://doi.org/10.1242/jcs.01165
- Shah R, Mahour GH, Ford EG, Stanley P. Partial splenic embolization. An effective alternative to splenectomy for hypersplenism. Am Surg. 1990;56:774.
- Shah V, Toruner M, Haddad F, Cadelina G, Papapetropoulos A, Choo K et al. Impaired endothelial nitric oxide synthase activity associated with enhanced caveolin binding in experimental cirrhosis in the rat. Gastroenterology. 1999;117:1222-1228. https://doi.org/10.1016/S0016-5085(99)70408-7
- Sherlock S. Disorders of the liver and the biliary system. Sherlock S, editor. 8 ed. Oxford: Blackwell; 1989:82-86.
- Shim KY, Eom YW, Kim MY, Kang SH, Baik SK. Role of the renin-angiotensin system in hepatic fibrosis and portal hypertension. Korean J Intern Med. 2018;33:453-461. https://doi.org/10.3904/kjim.2017.317
- Shrestha B, Prasai PK, Kaskas AM, Khanna A, Letchuman V, Letchuman S et al. Differential arterial and venous endothelial redox responses to oxidative stress. 2018;25(7):e12486. https://doi.org/10.1111/micc.12486
- Szczurek W, Szyguła-Jurkiewicz B. Oxidative stress and inflammatory markers – the future of heart failure diagnostics? Kardiochir Torakochirurgia Pol. 2015;12(2):145-149. https://doi.org/10.5114/kitp.2015.52856
- Tamura N, Ogawa Y, Chusho H, Nakamura K, Nakao K, Suda M et al. Cardiac fibrosis in mice lacking brain natriuretic peptide. Proceedings of the National Academy of Sciences of the United States of America. 2000;97(8):4239-4244. https://doi.org/10.1073/pnas.070371497
- Wong F, Watson H, Gerbes A et al. Satavaptan for the management of ascites in cirrhosis: efficacy and safety across the spectrum of ascites severity. Gut. 2012;61:108. https://doi.org/10.1136/gutjnl-2011-300157
- Xu RY, Liu B, Lin N. Therapeutic effects of endoscopic variceal ligation combined with partial splenic embolization for portal hypertension. World J Gastroenterol. 2004;10:1072. https://doi.org/10.3748/wjg.v10.i7.1072
- Yoshiji H, Kuriyama S, Yoshii J, Ikenaka Y, Noguchi R, Nakatani T, Tsujinoue H, Fukui H. Angiotensin-II type 1 receptor interaction is a major regulator for liver fibrosis development in rats. Hepatology. 2001;34:745-750. https://doi.org/10.1053/jhep.2001.28231
- Zhang J, Yang W, Hu B, Wu W, Fallon MB. Endothelin-1 activation of the endothelin B receptor modulates pulmonary endothelial CX3CL1 and contributes to pulmonary angiogenesis in experimental hepatopulmonary syndrome. Am J Pathol. 2014;184:1706-1714. https://doi.org/10.1016/j.ajpath.2014.02.027
- Zhou WC, Zhang QB, Qiao L. Pathogenesis of liver cirrhosis. World J. Gastroenterol. 2014;20:7312-7324. https://doi.org/10.3748/wjg.v20.i23.7312